Background: Since 2018, a dengue epidemic has been raging annually in Reunion Island, which poses the major problem of its morbidity and mortality. However, there is no consensus in the literature on factors associated with severity of illness. The objective of this study was to identify the factors associated with the occurrence of severe dengue (SD) according to the criteria adopted in 2009 by the World Health Organization (WHO), during the 2019 epidemic. Methodology/Principal findings: A total of 163 patients with RT-PCR-confirmed dengue were included in a multicenter prospective cohort study in Reunion Island between January and June 2019. Of these, 37 (23%) were classified as SD, which involves presentation dominated by at least one organ failure, and 126 (77%) classified as non-SD (of which 90 (71%) had warning signs). Confusion, dehydration, and relative hypovolemia were significantly associated with SD in bivariate analysis (p < 0.05). The factors associated with SD in multivariate analysis were a time from first symptom to hospital consultation over 2 days (OR: 2.46, CI: 1.42–4.27), a history of cardiovascular disease (OR: 2.75, 95%CI: 1.57–4.80) and being of Western European origin (OR: 17.60, CI: 4.15–74). Conclusions/Significance: This study confirms that SD is a frequent cause of hospitalization during dengue epidemics in Reunion Island. It suggests that cardiovascular disease, Western European origin, and delay in diagnosis and management are risk factors associated with SD fever, and that restoration of blood volume and correction of dehydration must be performed early to be effective. Trial registration: NCT01099852; clinicaltrials.gov Author summary: Dengue fever is a viral disease transmitted by mosquitoes that threatens more than half of the world's population. This re-emerging disease predominates in tropical areas such as Reunion Island, but is also expanding in formerly temperate regions. Some patients with dengue may have early signs (warning signs) of life-threatening complications (dengue hemorrhagic fever/shock syndrome) and require hospitalization, but only a minority of patients will progress to severe dengue. Identification of patients at risk is crucial to deliver optimal treatment without saturating intensive care units during epidemic periods. To this end, we followed 163 hospitalized patients with dengue during the 2019 epidemic in Reunion Island. Nearly a quarter of the patients had a severe form of the disease. The presence of cardiovascular disease, Western European origin, and delay in diagnostic and management were the main risk factors. This observation underlines the importance of an efficient detection of vulnerable populations and of an early management based on rehydration to prevent the occurrence of severe dengue in Reunion Island. [ABSTRACT FROM AUTHOR]